The Notch receptor signaling pathway has been implicated in multiple developmental processes including neurogenesis, vasculogenesis, myogenesis, and hematopoiesis. In hematopoiesis, Notch signaling can regulate stem cell differentiation and proliferation, myeloid maturation and is critical in the cell fate decision between T and B lymphocyte development. In addition, Notch signaling can induce T cell malignancies and most recently Notch signaling has been associated with B cell growth arrest and apoptosis. As a Fellow in Pediatric Hematology & Oncology at the Children's Hospital of Philadelphia (CHOP), I have begun a research project exploring the effect of Notch receptor signaling in human B cell malignancies. My preliminary data shows that several human B leukemia/lymphoma cell lines undergo cell cycle arrest and apoptosis following induction of Notch signaling either by Notch ligand, intracellular Notch1 or Hairy, a Notch downstream target gene. Over the next five years, as an instructor at CHOP, I will focus on my career development into an independent investigator. This proposal will provide the specific training and scientific approaches I will use to attain this goal during this mentored period. The first aim for this proposal is to determine which Notch pathway genes are expressed in normal human B cells and B cell malignancies. This will identify stages of B cell development during which Notch signaling may play a role and facilitate the design of methods of inducing Notch signaling. My second aim is to develop methods of activating Notch signaling in B cell malignancies, which would be accomplished by both extra- and intracellular means. This work will attempt to develop a potential therapeutic approach toward B cell malignancies. The final aim is to elucidate the mechanisms of Notch-mediated effects on B malignancies, which would not only provide insight into the cell-specific Notch-signaling pathways, but also may reveal additional approaches to manipulating the Notch signaling pathway. This research will be carried out in Dr. Warren Pear's laboratory. Dr. Pear is a faculty member at the University of Pennsylvania (UPenn) where he conducts research on many aspects of the Notch receptor pathway. Through CHOP & UPenn I have access to extensive core facilities and a great diversity of didactic opportunities. This K08 award will facilitate my career goals, namely to gain the knowledge and analytic skills to establish myself as a physician scientist and independent cancer researcher over the next five years.